Live long and prosper (under the right conditions)

Author

Restricting calorie intake seems to promote longer lives in a wide range of organisms, from microbes to mammals. Some determined youth-seekers are already adopting reduced-calorie diets in an attempt to extend their lifespans. But it’s not clear yet that these anti-aging effects apply to humans, and the mechanisms by which they work in other organisms are not fully understood.

In the March issue of GENETICS, David McCleary and Jasper Rine delve into the complex relationship between calorie restriction (CR), chronological aging, and the histone deacetylase Sir2. Some work suggests Sir2 lengthens lifespan in low-glucose conditions in yeast, while other work finds no such effect. The researchers made a clever observation that allowed them to resolve these conflicting results: almost all yeast are grown on 2% glucose, which they suggest is actually borderline CR, since natural yeast substrates contain substantially more glucose. They employed a broader range of glucose concentrations to more fully capture the range of effects of Sir2 and CR on aging in yeast.

McCleary and Rine found that the effect of SIR2 deletion depended on both glucose level—high or low—and the media type—rich, which is full of assorted nutrients and peptide fragments, or minimal, which contains a precise but simple combination of amino acids and nutrients. Deletion of SIR2 extended lifespan only in high-glucose minimal media. But in rich media, deletion of SIR2 had little effect in high glucose and decreased lifespan in low glucose. In search of a mechanism, the researchers considered the cellular function of Sir2: to deacetylate specific sites on histone tails, leading to heterochromatin formation and gene silencing at the affected locus. They found that Sir2-dependent silencing at one such site, the HML locus, was affected by the media—the silencing was destabilized by high glucose in rich media, but the opposite was true in minimal media.

These results suggest a role for Sir2 as a regulator of yeast aging, lengthening or shortening lifespan depending on the environment. It’s certainly conceivable that in lean times, a longer chronological lifespan would be handy, allowing for reproduction to be put off until conditions improve. But what benefit could there be for a single-celled organism to shave time off its life? It’s possible that the shortened lifespans seen in nutrient-rich environments simply result from faster metabolism, more activity, and more risk of cellular damage, causing aging. But another intriguing possibility is that group selection is at work—if a population of yeast consists of genetically close individuals, killing off some individuals would free up nutrients and space for the next, possibly even better-adapted, generation.